The hypoxic tight-skin mouse model of Group 3 pulmonary hypertension

Pulmonary hypertension (PH) arising from chronic lung disease and hypoxia is a deadly condition without cure. Small animal models using hypoxia are mild, and do not fully recapitulate human disease. The tight skin mouse (Tsk^+/-) possesses key characteristics of chronic lung disease, including emphysema. We sought to assess the lung vasculature in Tsk^+/- mice exposed to chronic hypoxia. Tsk^+/- mice and littermates were housed in normoxia or hypoxia for 4 weeks. Endpoint analysis included invasive measurement of right ventricular systolic pressure, histology, immunoblotting, and ELISA. Proliferation was measured in primary human pulmonary artery adventitial fibroblasts (PAAF) and pulmonary artery smooth muscle cells (PASMC). Tsk^+/- mice demonstrated significant emphysema. Following hypoxia, Tsk^+/- mice had severe PH as compared to wildtype. Tsk^+/- mice had elevated circulating high mobility group box-1 (HMGB1), which was further increased in hypoxia. Treatment with the HMGB1 antagonist, P5779, protected Tsk^+/- mice from PH. Tsk^+/- lungs displayed increased TGF-β signaling. In vitro, TGF-β stimulated HMGB1 expression in PAAF. HMGB1 in turn stimulated PAAF and PASMC proliferation. Tsk^+/- mice represent a robust model of Group 3 PH, driven by hypoxia, sensitized by elevated TGF-β signaling resulting in increased circulating HMGB1, stimulating PAAF and PASMC proliferation. The Tsk^+/- model represents a novel system for studying Group 3 PH.